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A phosphatase cascade by which rewarding stimuli control nucleosomal response

Abstract

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.

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Figure 1: Drugs of abuse and food self-administration induce nuclear accumulation of DARPP-32 in striatal neurons.
Figure 2: DARPP-32 undergoes continuous cyto-nuclear shuttling.
Figure 3: Phosphorylation at Ser 97 controls intracellular localization of DARPP-32.
Figure 4: Mutation of Ser 97 alters localization of DARPP-32, behavioural responses to drugs of abuse and motivation for food reward.
Figure 5: Role of nuclear DARPP-32 in the phosphorylation of histone H3 in striatal neurons.

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Acknowledgements

We thank M. Lambert for her help with time-lapse video; P. Ingrassia and P. Bernard for their help with mutant mice; and M. R. Picciotto, S. Cottecchia, J. P. Hornung, R. Luedtke, M. Takeda and Intracellular Therapies Inc. for reagents. This work was supported by Inserm, and by grants from Agence Nationale de la Recherche (05-NEUR-020-01), Fondation Bettencourt-Schueller (Coup d’élan) and Association pour la Recherche contre le Cancer (ARC-3118 and -7905) to J.A.G., from Fondation pour la Recherche Médicale (FRM) to D.H., a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to A.N., and grants from the National Institute on Drug Abuse (DA10044), the National Institute of Mental Health (MH74866), the US Department of Defense (W81XWH-05-1-0146), the Picower Foundation, the Michael Stern Parkinson’s Research Foundation and the US Army Medical Research Acquisition Activity (DAMD17-02-1-0705 and W81XWH-05-1-0146) to P.G. and A.C.N. A.S. was supported by Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie and FRM, and J.B.G. by FRM.

Author Contributions A.S. and Mi.M. performed experiments in vivo and in transfected cultures, immunofluorescence and molecular biology. E.V. conducted in vivo, behavioural and immunohistofluorescence experiments. A.S., E.V. and Mi.M. prepared the figures. A.N. performed the slice experiments, J.H.A. the phosphatase experiments, and Ma.M. the incentive learning experiments. J.B.G. and A.G.C. contributed to in vivo and immunohistofluorescence experiments, and K.B.C. and H.E. to cell culture experiments. O.F. provided advice and reagents. A.S., A.C.N., P.G., D.H. and J.A.G. were involved in the study design and manuscript writing. J.A.G. coordinated the study. All authors analysed data they generated, discussed results and commented on the manuscript. A.S., E.V. and Mi.M. contributed equally to this work.

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Correspondence to Jean-Antoine Girault.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-13 with Legends and Supplementary Table 1 with ANOVA analysis of results presented in Figures 1-4 (PDF 5984 kb)

Supplementary Movie

The file contains Supplementary Movie 1 with time lapse video of the nuclear translocation of DARPP-32-GFP in transfected a striatal neuron treated with leptomycin B (10 ng/ml). (AVI 6360 kb)

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Stipanovich, A., Valjent, E., Matamales, M. et al. A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453, 879–884 (2008). https://doi.org/10.1038/nature06994

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